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UCL

Les traitements immunosuppresseurs dans les rhumatismes systémiques. BR Lauwerys Service de Rhumatologie Cliniques Universitaires Saint-Luc Université catholique de Louvain. D.E.S. en Médecine Interne Année académique 2004-2005. UCL. Plan. Indications Induction versus Entretien

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UCL

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  1. Les traitements immunosuppresseurs dans les rhumatismes systémiques BR Lauwerys Service de Rhumatologie Cliniques Universitaires Saint-Luc Université catholique de Louvain D.E.S. en Médecine Interne Année académique 2004-2005 UCL

  2. Plan Indications Induction versus Entretien Cas réfractaires UCL

  3. Indications Tout rhumatisme systémique n’est pas grevé d’une diminution du pronostic vital. Pas d’indication de traitement immunosuppresseur dans LED avec arthrite / sérosite / rash / leucopénie SS limitée ou diffuse avec atteinte purement cutanée myopathies inflammatoires sans atteinte alvéolaire inflammatoire vasculite nécrosante avec FSS <1 UCL

  4. PAN Five Factor Score Proteinuria ≥ 1g/d Renal impairment CNS involvement GI involvement Cardiac involvement IV CPM only if FFS > 1 L. Guillevin et al.

  5. Prognostic value of FFS in necrotizing vasculitis Guillevin et al., 2001

  6. What is severe disease ? ACTIVITY Fever Gangrene Polyneuropathy Rash Arthritis Glomerulonephritis Cytopenias Thrombosis Grand mal DAMAGE Disease-related ESRD Deforming arthropathy Cutaneous scarring Cognitive impairment Optic atrophy Valvular disease APL antibody-related Iatrogenic UCL

  7. Clinical disease: MI, angina 6 % to 10 % Subclinical disease: 30 % to 40 % Risk factors: hypercholesterolaemia hypertension steroid use homocysteine The iceberg of atherosclerosis in SLE Bruce et al., Toronto

  8. Asanuma Y. et al.

  9. Induction versus maintenance therapy The concept EFFICACY The ideal remission - INDUCING treatment is efficient and not toxic TOXICITY The ideal remission - MAINTAINING treatment prevents relapses RELAPSES

  10. Which therapeutic goals in a newly diagnosed LN patient ? To achieve prompt remission(i.e. proteinuria < 1g/d in the absence of impaired renal function) To maintain remission andprevent renal flares(very common and associated with a poor outcome) To avoid renal impairment With minimal toxicity UCL

  11. Remission-inducing treatment GG Always consider dividing the dose by two! Gradual tapering down to ‘physiological doses’ IV GC ‘pulses’

  12. UCL

  13. Reduced bone mineral density in SLE UCL Houssiau et al., Br J Rheumatol 1996; 35: 244-247

  14. Reduced bone mineral density in SLE UCL Jardinet et al., Rheumatology 2000; 39: 389-392

  15. UCL

  16. UCL

  17. Remission-inducing treatment CYC Platinum standard Highly toxic (bladder, ovaries, bone marrow) Not always needed IV versus oral Low- versus high-dose IV UCL

  18. Cyclophosphamide therapy IV pulse Oral CPM SLE DPM PSS PAN MPA ... !?! WEGENER

  19. The NIH regimen The platinum standard for LN extended course (≥ 30 months) high (HD) IV CYC combined to GC superior to oral or IV GC alone Austin 1985, Boumpas 1992, Gourley 1996, Illei 2001

  20. The NIH regimen for LN IV CYC 0.75 - 1 g/m2 WBC nadir (d14): 1,500 - 4,000/ml monthly for 6 months quarterly for 1 year after CR IV MP 1 g/m2 monthly for 12 - 36 months

  21. p < 0.05 Austin et al., 1985 The 1st NIH trial

  22. The NIH regimen - Concern #1 Toxicity

  23. 5 56 % 2 % 4 3 Serum albumin (g/dl) 2 1 26 % 16 % 0 0.4 1.3 1.6 0.7 1 1.9 2.2 Serumcreatinine(mg/dl) The NIH regimen - Concern #2 Appropriate for mild/early cases ? Louvain LN Cohort (1985-2002)

  24. The changing picture of LN Study from Heidelberg Fiehn C. et al. Ann Rheum Dis 2003; 62: 435-9

  25. The NIH regimen - Concern #3 Does not prevent renal flares Illei et al., Arthritis Rheum 2002; 46: 995-1002

  26. Induction of remission Short-course (a few months) with a « incisive » immunosuppressant Maintenance of remission Long-term use (5 years ?) of a « safe » immunosuppressant The revisited standard treatment of LN Sequential use of cytotoxic therapies UCL

  27. Euro-Lupus Nephritis Trial Induction of remission CYC IV NIH regimen versus CYC IV mini-pulses (6 x 500 mg; q2weeks) Maintenance of remission AZA UCL

  28. EURO-LUPUS regimen INDUCTION 3 x 750 mg IV MP qd 6 x 500 mg IV CPM q2w 0.5 mg pred./kg/d 1 month MAINTENANCE AZA 2 mg/kg/d at 3m taper GC by 2.5 mg q2w plateau at 5-7.5 mg UCL

  29. 100 90 80 70 60 50 0 0 12 24 36 48 60 ELNT - Treatment failure LD HD Free of Failure (%) HD LD HR: 0.79 (CIs: 0.30-2.14) Follow-up (months) UCL Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131

  30. 1 0 . 8 0 . 6 0 . 4 0 . 2 0 0 2 4 1 2 3 6 4 8 6 0 F o l l o w - u p ( m o n t h s ) ELNT - Remission LD HR: 1.26 (CIs 0.72-2.21) HD Probability of remission HD LD Remission: < 10 RBC/hpf, 24-h proteinuria < 1g, no DSC UCL Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131

  31. ELNT - Early response to therapy Adjustment for baseline creatinine by ANCOVA p = 0.018 5 ANOVA p = 0.0003 p = 0.011 4 3 2 1 0 Good renal outcome Houssiau et al., Arthritis Rheum, 2004; 50: 3934-3940 24h proteinuria (g) Month 6 Month 3 Baseline UCL Poor renal outcome

  32. Multivariate analysis of predictors of good long-term renal outcome Houssiau et al., Arthritis Rheum, 2004; 50: 3934-3940

  33. Baseline Followup 20 p = 0.013 p = 0.001 15 Activity index (mean ± SEM) 10 5 0 HD group LD group ELNT - Pathology UCL Houssiau et al., Arthritis Rheum, 2004; 50: 3934-3940

  34. ELNT - Pathology UCL Houssiau et al., Arthritis Rheum, 2004; 50: 3934-3940

  35. ELNT - Severe infections UCL Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131

  36. Lesson from the ELNT A short- course of low-dose IV CYC might be enough in the induction phase UCL

  37. IV CYC therapy Vaccinations are safe and efficient in patients with systemic rheumatic disorders. Vaccination with pneumococcal antigens is required before starting CYC therapy Life attenuated vaccines should be avoided in immunocompromised patients UCL

  38. Induction versus maintenance therapy Can we do better ?

  39. Renal remission rate

  40. Renal relapse rate 46 LN patients diagnosed and followed-up at UCL (64 ± 49 months) Relapse rate: 37 % 40 ± 24 (mean ± SD) months after diagnosis of LN 80 % on AZA by the time of flaring UCL El Hachmi et al. , Lupus 2003, 12: 692-696

  41. Chronic renal impairment rate

  42. Prognostic factors Afro-American race Poor socio-economic status Non-compliance Severe clinical onset High CI, AI Uncontrolled hypertension Renal relapse Poor initial response to therapy

  43. Toxicity

  44. LN: key figures Remission rate : 80% Relapse rate: 35% ESRD: 5-10% Side-effects: +++

  45. LN impacts survival Euro-Lupus Project N- N+

  46. Unsolved issues Is IV CYC the best choice during the induction phase ? UCL

  47. MMF: a new star twinkling in the sky Lymphocytes, unlike most eukariotic cells, lack the salvage pathway that also generates GTP

  48. Inhibitory properties of MPA lymphocyte proliferation vascular smooth muscle proliferation mesangial cell proliferation inhibits glycosylation iNOS renal cortical expression

  49. Can MMF replace IV CYC for induction ? FDA-sponsored Study Short-term (24 weeks) remission-induction study comparing MMF and NIH IV CYC in 140 LN patients MMF: maximum tolerated dose, ad 3 g/d; 63% reached 3 g ! Ginzler E. et al. ACR meeting 2003

  50. FDA-sponsored Study Ginzler E. et al. ACR meeting 2003 CR: normal serum creatinine, proteinuria < 0.5 g/d and inactive urinary sediment

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